Substituted 9-amino-spiro[cycloalkyl[B]quinoline-2,1&#39;cycloalkanes]

ABSTRACT

There are disclosed compounds having the formula ##STR1## wherein m is 1 or 2; n is 1 or 2; p is 1-5; x is hydrogen, loweralkyl, cycloalkyl, loweralkoxy, halogen, hydroxy, nitro, trifluoromethyl, formyl, loweralkylcarbonyl, arylcarbonyl, --SH, loweralkylthio, --NHCOR 2  or --NR 3  R 4  where R 2  is hydrogen or loweralkyl, and R 3  and R 4  are independently hydrogen, loweralkyl or cycloalkyl; R is hydrogen, loweralkyl or loweralkylcarbonyl; and R 1  is hydrogen, loweralkyl, loweralkylcarbonyl, aryl, diloweralkylaminoloweralkyl, arylloweralkyl, diarylloweralkyl, oxygen-bridged arylloweralkyl or oxygen-bridged diarylloweralkyl; stereo, optical and geometrical isomers thereof, and pharmaceutically acceptable acid addition salts thereof, which are useful for enhancing memory.

This is a division, of co-pending application Ser. No. 031,825, filedMar. 30, 1987, now U.S. Pat. No. 4,762,841.

This invention relates to compounds having the formula ##STR2## whereinm is 1 or 2; n is 1 or 2; p is 1-5; X is hydrogen, loweralkyl,cycloalkyl, loweralkoxy, halogen, hydroxy, nitro, trifluoromethyl,formyl, loweralkylcarbonyl, arylcarbonyl, --SH, loweralkylthio, --NHCOR₂or --NR₃ R₄ where R₂ is hydrogen or loweralkyl, and R₃ and R₄ areindependently hydrogen, loweralkyl or cycloalkyl; R is hydrogen,loweralkyl or loweralkylcarbonyl; and R₁ is hydrogen, loweralkyl,loweralkylcarbonyl, aryl, diloweralkylaminoloweralkyl, arylloweralkyl,diarylloweralkyl, oxygen-bridged arylloweralkyl or oxygen-bridgeddiarylloweralkyl; stereo, optical and geometrical isomers thereof, whichare useful for enhancing memory, methods for synthesizing them, andpharmaceutical compositions comprising an effective memory enhancingamount of such a compound, and a method of increasing the cholinergicfunction in mammals which comprises the administration of an effectiveamount of such a compound.

This invention also relates to compounds having the formulas ##STR3##wherein X, m, n, and p are as defined above, R₅ is hydrogen orloweralkyl, and Y is halogen, hydroxy or loweralkoxy, which are usefulas intermediates for synthesizing the compounds of Formula I.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, optical and geometricalisomers thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following definitions shall apply throughout the specification andthe appended claims.

Unless otherwise stated or indicated, the term loweralkyl denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said alkyl include methyl, ethyl, n-propyl, iso-butyl,pentyl, and hexyl.

Unless otherwise stated or indicated, the term cycloalkyl denotes asaturated ring containing 3 to 7 carbon atoms. Examples of saidcycloalkyl include cyclopropyl, cyclohexyl and cycloheptyl.

Unless otherwise stated or indicated, the term loweralkoxy denotes astraight or branched alkoxy group having 1 to 6 carbon atoms. Examplesof said loweralkoxy include methoxy, ethoxy iso-propoxy, sec-butoxy andstraight and branched chain hexyloxy.

Unless otherwise stated or indicated, the term halogen shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term aryl shall mean anunsubstituted phenyl group or a phenyl group substituted with 1, 2 or 3substituents each of which being independently loweralkyl, loweralkoxy,halogen, hydroxy, trifluoromethyl phenoxy or benzyloxy.

Unless otherwise stated or indicated, the term oxygen-bridged shallsignify the fact than an oxygen atom is present between aryl andloweralkyl groups and/or an oxygen atom has replaced a methylene groupin the lowerakyl group, with the proviso that said methylene group isnot alpha to the amino nitrogen carrying the groups R and R₁. Thus, forinstance, examples of oxygen-bridged arylloweralkyl include3-phenoxypropyl and 4-phenoxybutyl, and examples of oxygen-bridgeddiarylloweralkyl include 2-[bis(4-fluorophenyl)methoxy]ethyl and2-[bis(3-fluorophenyl)methoxy]ethyl.

The compounds of this invention are prepared by utilizing one or more ofthe steps described below.

In order to simplify the description of the synthetic schemes, thedescription will be presented with specific reference to the situationwhere m=1, n=2 and p=3, but it will readily be understood that thesynthetic schemes can also be applied to the other situations by makingobvious modifications where necessary.

Throughout the description of the synthetic steps, the definitions of X,Y, R and R₁ through R₅ are as given above unless otherwise stated orindicated.

STEP A

A compound of formula IIa can be prepared by reacting a compound ofFormula IV with spiro[4.5]decan-7-one. Said reaction can be conducted ina suitable solvent such as benzene, toluene or xylene at a temperatureof about 80°-150° C. in the presence of an acid catalyst such asp-toluene sulfonic acid, benzenesulfonic acid or methanesulfonic acid.##STR4##

STEP B

A compound of Formula IIIa can be prepared by reacting compound IIa withphosphorous pentoxide in the presence of a high boiling tertiary aminesuch as N,N-dimethylcyclohexylamine. Said reaction can be conductedwithout additional solvent at a temperature of about 170°-220° C.##STR5##

STEP C

A compound of Formula IIIb can be prepared by reacting compound IIIawith phosphorous oxychloride and phosphorous pentachloride. Saidreaction can be conducted at a temperature of about 100°-150° C.##STR6##

The bromine analogue of compound IIIb can be prepared in a similarmanner, namely, for instance by reacting compound IIIa with phosphorousoxybromide and phosphorous pentabromide. The fluorine and iodineanalogues of compound IIIa can be prepared by replacing the chlorineatom of compound IIIa with fluorine or iodine in a routine manner knownto the art.

STEP D

A compound of Formula VI can be prepared by reacting compound IIIb withan amine of formula V. Said reaction can be conducted at a temperatureof 120°-220° C. in the presence of a hydroxylated aromatic compound suchas or phenol or cresol. ##STR7##

Steps A through D can be combined into a single step. Thus compound VIcan be obtained by heating together a mixture of phosphorous pentoxide,N,N-dimethylcyclohexylamine and the hydrochloride of maine V and thenadding compound IV followed by spiro[5.5]undecan-3-one. Said reactioncan be carried out at a temperature of 150°-250° C.

STEP E

A compound of Formula VIa can be prepared by reacting ananthranilonitrile of Formula VII with spiro[4.5]decan-7-one. Saidreaction can be conducted in the presence of a Lewis acid such as zincchloride, without solvent at a temperature of about 80°-150° C. or in asolvent such as 1,2-dichloroethane or nitrobenzene, again at atemperature of about 80°-150°. ##STR8##

The compounds of Formula I of the present invention can be used for thetreatment of various memory dysfunctions characterized by decreasedcholinergic function, such as Alzheimer's disease.

This utility can be ascertained by determining the ability of thesecompounds to inhibit the activity of the enzyme acetylcholinesterase andthereby increase the acetylcholine levels in the brain.

This utility can also be ascertained by determining the ability of thesecompounds to restore cholinergically deficient memory in the DarkAvoidance Assay. In this assay mice are tested for their ability toremember an unpleasant stimulus for a period of 24 hours. A mouse isplaced in a chamber that contains a dark compartment; a srongincandescent light drives it to the dark compartment, where an electricshock is administered through metal plates on the floor. The animal isremoved from the testing apparatus and tested again, 24 hours later, forthe ability to remember the electric shock.

If scopolamine, an anticholinergic that is known to cause memoryimpairment, is administered before an animal's initial exposure to thetest chamber, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. This effect ofscopolamine is blocked by an active test compound, resulting in agreater interval before re-entry into the dark compartment.

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsules or tablets parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteralpreparations can be enclosed in disposable syringes or multiple dosevials made of glass or plastic.

Examples of the compounds of this invention include:

9-amino-3,4-dihydrospiro[acridine-2(1H),1'-cyclopropane];

9-amino-3,4-dihydro-6-trifluoromethylspiro[acridine-2(1H),1'-cyclopropane];

3,4-dihydro-9-methylaminospiro[acridine-2(1H),1'-cyclopropane];

9-benzylamino-3,4-dihydrospiro[acridine-2(1H),1'-cyclopropane];

9-benzylamino-7-chloro-3,4-dihydrospiro[acridine-2(1H),1'-cyclopropane];

9-anilino-3,4-dihydrospiro[acridine-2(1H),1'-cyclopropane];

9-amino-3,4-dihydrospiro[acridine-2(1H),1'-cyclopentane];

9-amino-6-chloro-3,4-dihydrospiro[acridine-2(1H),1'-cyclopentane];

9-amino-3,4-dihydro-6-methoxyspiro[acridine-2(1H),1'-cyclopentane];

3,4-dihydro-9-methylaminospiro[acridine-2(1H),1'-cyclopentane];

3,4-dihydro-6-fluoro-9-methylaminospiro[acridine-2(1H),1'cyclopentane];

9-(4-chlorobenzylamino)-3,4-dihydrospiro[acridine-2(1H),1'-cyclopentane];

9-anilino-3,4-dihydrospiro[acridine-2(1H),1'-cyclopentane];

3,4-dihydro-9-(2-fluoroanilino)spiro[acridine-2(1H),1'-cyclopentane];

9-amino-3,4-dihydrospiro[acridine-2(1H),1'-cyclohexane];

7-acetamido-9-amino-3,4-dihydrospiro[acridine-2(1H),1'-cyclohexane];

9-amino-3,4-dihydro-7-methoxyspiro[acridine-2(1H) 1'-cyclohexane];

7-chloro-3,4-dihydro-9-methylaminospiro[acridine-2(1H),1'-cyclohexane];

3,4-dihydro-9-(3-fluorobenzylamino)spiro[acridine-2(1H),1'-cyclohexane];

3,4-dihydro-9-(3-methoxybenzylamino)spiro[acridine-2(1H),1'-cyclohexane];

3,4-dihydro-9-(4-methoxyanilino)spiro[acridine-2(1H),1'-cyclohexane];

9-amino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

9-amino-1,3-dihydro-6-fluorospiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

9-amino-1,3-dihydro-7-methoxyspiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

7-acetamido-9-amino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

1,3-dihydro-9-methylaminospiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

1,3-dihydro-9-propylaminospiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

1,3-dihydro-9-(4-methylbenzylamino)spiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

9-(3,4-dichlorobenzylamino)-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

9-(3,4-dichloroanilino)-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1'-cyclopentane];

9-amino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1'-cyclohexane];

1,3-dihydro-9-ethylaminospiro[cyclopenta[b]quinoline-2,1'-cyclohexane];

9-benzylamino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1'cyclohexane];and

9-anilino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1'-cyclohexane].

I claim:
 1. A compound having the formula ##STR9## wherein m is 1 or 2;n is 1 or 2; p is 1-5; X is hydrogen, loweralkyl, cycloalkyl,loweralkoxy, halogen, hydroxy, nitro, trifluoromethyl, formyl,loweralkylcarbonyl, arylcarbonyl, --SH, loweralkylthio, --NHCOR₂ or--NR₃ R₄ where R₂ is hydrogen or loweralkyl, and R₃ and R₄ areindependently hydrogen, loweralkyl or cycloalkyl; and Y is halogen,hydroxy or loweralkoxy.